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Myc and PI3-k induced gene expression in RWPE1

ABSTRACT: Analysis of transcriptional changes during Myc or PI3K induced oncogenic transformation in RWPE1 cells (benign prostate epithelial cell line). The aim of the present study was to identify key epigenetic gene silencing events that occur during the oncogenic transformation events, hence emphasis was placed on downregulated genes. Results provide important information on which are the tumor suppressive pathways or genes that will be epigenetically silenced by during Myc or PI3K induced oncogenic transformation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE43686 | GEO | 2015/05/20

SECONDARY ACCESSION(S): PRJNA187057

REPOSITORIES: GEO

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Project description:Somatic NOTCH1 mutations are found in ~60% of T lineage acute lymphoblastic leukemias (T-ALLs). Notch1 is cleaved by γ secretase to generate activated Notch intracellular domain (NICD) proteins. The NOTCH1 mutations found in T-ALL constitutively activate Notch1 signaling by increasing NICD levels. Genetic alterations in components of the Ras/PI3 kinase (PI3K)/Akt pathway are also highly prevalent in T-ALL, and often coexist with NOTCH1 mutations. Exposing a T-ALL cell line to the PI3 kinase (PI3K) inhibitor GDC-0941 generated drug resistant clones that down-regulated NICD expression. To address the in vivo relevance of this unexpected observation, we transplanted primary wild-type (WT) and KrasG12D mutant T-ALLs into recipient mice, and treated them with GDC-0941 alone and in combination with the MEK inhibitor PD0325901 (PD901). Although many leukemias responded dramatically to these targeted agents in vivo, drug-resistant clones invariably emerged. Multiple resistant T-ALLs lost NICD expression through mechanisms that included loss of Notch1 mutations found in the parental T-ALL. These GDC-0941-resistant leukemias exhibited reduced expression of many Notch1 target genes, elevated levels of phosphorylated Akt (pAkt), and displayed cross-resistance to γ secretase inhibitors (GSIs). Consistent with these data, inhibiting Notch1 activity in T-ALL cells enhanced PI3K signaling, providing a likely mechanism for in vivo selection against clones with Notch1 pathway activation. Thus, oncogenic Notch1 mutations that promote clonal outgrowth during malignant transformation unexpectedly “switch” to become deleterious during treatment with a PI3K inhibitor. These data advance our understanding of T-ALL pathogenesis and have implications for implementing new therapeutic regimens. We analyzed 28 mouse T-ALL samples obtained after in vivo treatment with GDC-0941 alone or GDC-0941 + PD0325901. These T-ALL samples are either Kras wild type or harbor a KrasG12D mutations.

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Myc and PI3-k induced gene expression in RWPE1

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